The tetraazamacrocycles are well-known platforms for generating ligand systems for coordinating metal ions and the N-carboxyalkyl and N-phosphonoalkyl derivatives are popular in inorganic chemistry for forming some of the most stable metal complexes. This class of ligands plays an important role in several industrial and biomedical processes where metal chelation is desired. For example, derivatives such as 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetracetic acid (DOTA) and 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetramethylene-phosphonic acid (DOTP) have wide applicability in demetallation of water and other fluid systems in industry. Further, the metal complexes have recently been found useful in both imaging and therapeutic applications whereby otherwise toxic metal ions are rendered safe by complexing with these ligands. See, for example, A E Martell and R D Hancock, “Metal Complexes in Aqueous Solutions”, Springer Verlag, 1996, chapter 5.
In medicine, the polyazamacrocyclic ligands have been widely used as chelators for a variety of transition metals. The macrocyclic polyaminocarboxylates such as DOTA and 1,4,8,11-tetraazacyclo-tetradecane-1,4,8,11-tetracetic acid (TETA) are known to form highly stable metal complexes due to their highly preorganized macrocyclic ligand framework. The macrocyclic ligands can form complexes with radionuclides such as Tc-99m, In-111, Ga-67, Y-90, Re-188, Sm-153 or other radioactive metal ions to yield pharmaceuticals useful in radionuclide imaging and therapy. The ligands can form complexes with metal ions heavier than iodine to generate products useful in X-ray imaging. Further, the ligands can bind paramagnetic metal ions such as Gd+3, Mn+2, Fe+3, Cr+3 to yield magnetic resonance imaging (MRI) agents. In special cases, the macrocycles can be specially modified so as to both bind a metal ion and then deliver the metal complex compounds to specific targets for improved imaging or targeted therapy. Such dual function ligands are often referred to as bifunctional ligands.
Cyclen, 1,4,7,10-tetraazacyclododecane, is the scaffold commonly used for generating DOTA, a key ligand for formation of metal complexes hereinbefore described. Cyclen is particularly useful for generating the triscarboxymethylated DO3A, 4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecane, a ligand by itself and also a key intermediate which can be variously derivatized at the free macrocyclic nitrogen for formation of a range of bifunctional ligands, the metal complexes of which are useful for imaging and therapy. For example, in U.S. Pat. No. 4,877,600, Bonnemain et al. disclosed the gadolinium complex of DOTA for imaging/MRI. In U.S. Pat. No. 4,885,363, Tweedle et al. similarly disclosed a gadolinium complex of DO3A-HP, a DO3A-derivative in which the free macrocyclic N was alkylated with 2-hydroxypropyl, for imaging. Similarly, in U.S. Pat. No. 5,994,536, Petrov et al. disclosed another gadolinium complex for MRI, Gd-DO3A-butriol in which the alkyl substituent at the free macrocyclic N is 2,3-dihydroxy-1-(hydroxymethyl)propyl. Others have disclosed other targetable DO3A-derivatives; see, e.g., Platzek et al., U.S. Pat. No. 6,576,222.
Typically, precursors of bifunctional chelates are synthesized by alkylation of an esterified DO3A, such as DO3A tris(t-butyl ester), in a strong base, such as an alkali metal hydroxide or an alkali metal carbonate. For example, in U.S. Pat. No. 6,576,222 Platzek et al. disclosed alkylation of DO3A in 6N potassium hydroxide (KOH). In U.S. Pat. No. 4,885,363, Tweedle et al. similarly disclosed N-alkylations of DO3A in excesses of sodium hydroxide (NaCH) or potassium carbonate (K2CO3). Platzek et al. and Tweedle et al. then isolated the macrocycle as a free base by filtration and/or chromatography, providing low yields and/or oils that are hard to handle for subsequent reactions. Alternatively, cyclen may be monoalkylated first with a unique group of interest, for example a bifunctional targeting group or a linker, and then derivatized at the other three nitrogen atoms to produce a DO3A-type moiety. See for example, Kruper et al., J. Org. Chem., 1993, 58, 3869-3875, In the process described by Kruper et al., an HBr salt of the monoalkylated macrocycle was generated which required additional purification by chromatography, hence lowering their yield.